Prostate cancer has become one of the most frequently diagnosed cancers in men in the United States and a major cause of cancer morbidity and mortality. The transcendent objective of the Johns Hopkins Prostate Cancer SPORE is to reduce prostate cancer incidence and mortality via the focused pursuit of translational research in prostate cancer. This competitive renewal proposal, which has been revised in response to reviewer critiques, contains five Translational Research Projects, four Core Resources, two Career Development Projects, and two Developmental Research Projects: Dr. John Isaacs' Research Project exploits the enzyme activities of prostate-specific antigen (PSA) and human glandular kallikrein-2 (hGK2) for the selective activation of prostate-specific pro-drugs, Dr. Carducci's Research Project targets the use of inhibitors of DNA methylation along with inhibitors of histone deacetylation to restore "silenced" gene expression in prostate cancer cells, Dr. Rodriguez's Research Project builds on an already successful translational research program, the development of cytolytic adenoviruses as prostate cancer gene therapy, by attempting to improve both the selectivity and lethality of replication-restricted cytolytic adenoviruses for prostate cancer cells in such a way as to increase prostate cancer treatment efficacy, Dr. Nelson's Research Project pursues the development of sulforaphane as a prostate cancer prevention agent, and Dr. William Isaacs' Research Project explores the contribution of genetic determinants of oxidative cell and genome damage and repair to prostate cancer risk in population studies. Each of the Research Projects features translation of innovative scientific concepts to human clinical trials or to population studies. The Research Projects are supported by Core Resources for Administration, for a Tissue Archive, for Biomarker Development, and for Biostatistics.